Oral pharmaceutical formulation containing ibandronate

ABSTRACT

The invention is directed to well-tolerated pharmaceutical compositions for oral application, containing ibandronate or a physiologically tolerable salt thereof as active substance, the administration form consisting of an active substance-containing inner portion enclosed in such fashion by a coat free of active substance that rapid release of the active substance takes place.

The invention relates to pharmaceutical formulations of ibandronate orits physiologically tolerable salts for oral application, and toprocesses for producing same.

The active substance ibandronaic acid(1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1,1-diphosphonic acid) andits salts (ibandronates), respectively, are among the class ofdiphosphonic acids which, in particular, are of interest in thetreatment of bone diseases and particular disorders in the calciummetabolism such as hypercalcaemia, osteoporosis, tumor osteolysis orPaget's disease. In the treatment of the diseases mentioned, theseactive substances must be administered frequently and over a long periodof time and therefore, the aim should be especially oral application inaddition to intravenous application since it is the former which is moreaccepted by many patients.

Fundamentally, however, oral treatment is generally complicated by thewell-known problems with oral tolerability of diphosphonic acids.Diphosphonic acids or their physiologically safe salts, and particularlyaminodiphosphonic acids are known to give rise to irritations of theupper gastrointestinal tract (Fleisch H., Bisphosphonates in BoneDisease, Herbert Fleisch, Bern 1993, pp. 126-131). The same applies fordiphosphonates which are also ingested at relatively low dosages of,e.g., less than 50 mg per single administration form. WO 93/09785 pointsout that the active substance risedronate([1-Hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate), for example, maygive rise to erosions and ulcerations in the upper sections of thedigestive tract. Various references allude to the gastrointestinalintolerability of the active substances pamidronate (Dodwell D. et al.,Biochemical Effects, Antitumor Activity and Pharmacokinetics of Oral andIntravenous Pamidronate (APD) in the Treatment of Skeletal BreastCancer., Br. J. Cancer 62, 496 (1990)) and tiludronate (Reginster J. Y.,Efficacy and Tolerability of a New Formulation of Oral Tiludronate(Tablet) in the Treatment of Paget's Disease of Bone, J. Bone Miner.Res. 9, 615-619 (1994)). In addition, it is also well-known thatmotility disorders may occur when swallowing the tablets and/or thetablets to be ingested get stuck due to the particular anatomicsituation in the oesophagus. This may give rise to odynophagia oroesophageal strictures as well. Frequently, this is the case withelderly patients or with patients who, due to their disease, are forcedto take the required tablets predominantly in a lying position.

Accordingly, in order to solve these problems, the art demanded thatfundamentally, orally available administration forms be coated with agastric juice-resistant film so that the active substance is releasedonly subsequent to the passage through the stomach and thus, irritationsof the stomach and the oesophagus would be avoided. For example, WO95/08331 describes administration forms by which it is possible toreduce the irritating potential of alendronate and other diphosphonatesin oral application.

Due to the above-described oral intolerability of diphosphonates, therehas been a search for more tolerable administration forms for a numberof these active substances. In particular, oral administration formscoated with gastric juice-resistant coatings have been developed in thiscontext. Such coatings are the choice in protecting the upper sectionsof the gastrointestinal tract, particularly the oesophagus or thestomach, from intolerable active substances. These gastricjuice-resistant coatings on solid oral administration forms dissolveonly at higher pH values of about 5.5 on, so that in the acidic gastricmedium, being at a pH value far below 5.5, no active substance will bereleased from the administration form and thus, the stomach is protectedfrom irritations caused by the active substance. As no active substanceis released in the stomach, it is possible at the same time to preventoesophagitis or other irritations of the oesophagus caused by therefluxing gastric contents containing active substance. As aconsequence, DE 59 005 517 (EP 421,921) describes a gastricjuice-resistant oral administration form for pamidronate which issuitable in reducing the risk of gastric ulcerations. Furthermore, WO93/09785 illustrates such an administration form for risedronate, WO95/08331 for alendronate and other diphosphonates.

The potential advantages of the gastric juice-resistant administrationforms are contrasted by a number of drawbacks. Thus, resorption withthese administration forms may be reduced as compared to forms releasingin a pH-independently rapid fashion, or resorption is substantially morevariable as compared to conventional forms, thus impairing orjeopardizing therapeutical safety. Therefore, there is a demand inalternative administration forms for these active substances in order toavoid the disadvantages of the gastric juice-resistant forms andnevertheless, be capable of providing sufficient protection from theseaminobisphosphonates having aggressive effects on the gastric mucosa.

Surprisingly, it was found that improved oral tolerability in the caseof the ibandronate active substance is already achieved when peroraladministration forms are coated with an adjuvant coating or film in suchfashion that the active substance is dissolved within a short period oftime and correspondingly high local concentrations of active substanceare achieved in the stomach. The film dissolving upon contact withdigestive juice is preferably a coating which dissolvespH-independently. The adjuvant coating may be coated using methodscommon in pharmaceutical technology. Although this coating does notprevent dissolution of ibandronate in the stomach, it was surprisingthat no significant side effects were observed in clinical studies usingibandronate even at high dosages. Despite the fact that theadministration forms are coated with a film which quickly releases theactive substance, there are no irritations in the oesophagus whenswallowing the tablets, and oesophagitis does not occur. This isparticularly advantageous since the administration forms of theinvention are also well-tolerated by patients lying in bed.

According to the invention, solid oral formulations of ibandronate areprovided, consisting of a core containing the active substance, which iscoated with an adjuvant coating free of active substance, which eitherdissolves independently of the pH value or is removed from the solidoral formulation upon contact with digestive juice. In this way,relatively rapid disintegration of the drug form and release of theactive substance within a short period of time are ensured, whereby highlocal concentrations of the active substance are achieved. The coatingmay be applied using methods such as film coating, press coating, tabletcoating, encapsulating or micro-encapsulating. The release of activesubstance from the appropriately coated solid administration forms fororal application, such as film tablets, coated tablets, laminatedtablets, capsules, or microcapsules, takes place more rapidly ascompared to the gastric juice-resistant administration forms. Accordingto the invention, at least 30% of the contained ibandronate dose, butpreferably at least 75% and, in particular, at least about 85% isreleased rapidly and independently of the pH value within thephysiological pH range. Preferably, the time period required to achievethese release percentages is less than 2 hours, more preferably lessthan 1 hour, with about 1-30 minutes being particularly preferred. It isparticularly preferred that the release is about 80-90% within a timeperiod of up to 15 minutes. Conveniently, the release of activesubstance is estimated within the scope of an in vitro experimentaccording to well-known standardized procedures.

Surprisingly, rapid release of the active substance does not result inthe undesirable side effects usually known for diphosphonic acids asdescribed above, despite the high local concentrations of activesubstance (i.e., despite the high gradient of active substance) therebygenerated in the stomach. Rather, it was found that despite the rapidrelease of active substance, the problem of occurring gastrointestinaldisorders is avoided, quite surprisingly. Furthermore, it has beenobserved that among patients treated with such rapidly releasingadministration forms of ibandronate, there were significantly less casesof nausea, vomiting, pain or diarrhoea than otherwise observed whenadministering aminobisphosphonates.

The coatings with rapid release of active substance in the meaning ofthe invention can be applied to all the suitable peroral administrationforms such as tablets, capsules, coated tablets, pellets, granulates orpowders. These administration forms consist of mixtures of activesubstances with pharmaceutical adjuvants or of pure active substances.Coating may be performed using various methods common in pharmacy. Forexample, suitable methods use tablet coating units, film coating units,tablet presses for press coating, encapsulating machines, ormicro-encapsulating units, such as facilities for spray freezing andspray embedding, facilities for producing simple or complex coacervates.

In the meaning of the invention, pharmaceutically common orphysiologically safe polymers are possible as film-forming agents.Film-forming agents in the meaning of the invention are derived from,e.g., the groups of cellulose derivatives, dextrins, starches and starchderivatives, polymers based on other carbohydrates and derivativesthereof, natural gums such as gum arabic, xanthans, alginates;polyacrylic acid, polyvinyl alcohol, polyvinyl acetate,polyvinylpyrrolidone, polymethacrylates and derivatives thereof(Eudragit®), chitosan and derivatives thereof, shellac and derivativesthereof. In addition to these film-forming agents, substances from theclass of wax and fat substances may be used to produce the coatingsaccording to the invention.

Preferably, the soluble alkyl- or hydroxyalkylcellulose derivatives suchas methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, or sodium carboxymethylcellulose arepossible as cellulose derivatives. In a preferred variant of anembodiment of the invention, methylhydroxypropylcellulose is employed.The usual cellulose derivatives suitable for pharmaceutical purposes,with varying degrees of substitution and/or varying molecular weightscorresponding to varying viscosity levels of the aqueous solutions, maybe used as suitable film-forming agents on the basis of cellulose.Likewise, insoluble cellulose derivatives such as ethylcellulose may beemployed.

In the case of polymethacrylates, cationic copolymerizates ofdimethylaminoethyl methacrylate with neutral methacrylic esters(Eudragit® E), copolymerizates of acrylic and methacrylic esters havinga low content of quaternary ammonium groups (described in “AmmonioMethacrylate Copolymer Type A or Type B” USP/NF, Eudragit® RL and RS,respectively), and copolymerizates of ethyl acrylate and methylmethacrylate with neutral character (in the form of an aqueousdispersion, described in “Polyacrylate Dispersion 30 Per Cent” Ph. Eur.,Eudragit® NE 30 D) are possible.

Similarly, the use of film-forming agents usually employed in theproduction of gastric juice-resistant films is possible as long aspH-independently rapid release of the active substance from theappropriately coated administration form, as described above, isensured, e.g., by a thin layer thickness of the coating or othermeasures such as an extremely high percentage of pore-forming agents orthe like. Anionic copolymerizates of methacrylic acid and methylmethacrylate (described in “Methacrylic Acid Copolymer, Type C” USP/NF,Eudragit® L and S, respectively, or in the form of the Eudragit® L 30 Daqueous dispersion), acidic cellulose derivatives such as celluloseacetate phthalate, cellulose acetate trimellitate andmethylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate,etc. may be used as such films.

In principle, all the film-forming agents may be employed alone as wellas in mixtures of two or more film-forming agents.

If required, the films may contain additional adjuvants such asplasticizers, pore-forming agents, filling agents, colorants, pigments,antifoam agents, antistick agents, and the like.

According to the invention, polymers and adjuvants possibly required inaddition, as were described in the preceding paragraph, are possible forpress coating as far as they can be processed by means of press coatingtechnology. In addition, all the pharmaceutically common orphysiologically tolerable adjuvants which are suited to form a closedcoat by press coating on the drug forms to be covered may be used in themeaning of the invention. In particular, these include adjuvants as arecommon in conventional tabletting, specifically filling agents from thegroup of carbohydrates such as lactose, saccharose, glucose and othersugars, microcrystalline cellulose, starches and starch derivatives,sugar alcohols such as mannitol, sorbitol, xylitol, inorganic fillingagents such as phosphates and carbonates. According to the invention,other adjuvants as required in the production of conventional tablets,such as binding agents, disintegrants, flow agents, release agents,taste improvers, pigments, and coloring agents may be contained inaddition to the filling agents.

According to the invention, all the adjuvants described above may beemployed for tablet coating, in principle. In addition, specialadjuvants for tablet coating may be employed according to the invention,such as palatinite, bentonite, calcium sulfate as filling agents,polyethylene glycol or polyethylene glycol fatty acid esters as releaseagents, colloid silicic acid as drying agent and structuring agent,magnesium oxide as spreading powder, pharmaceutically common orphysiologically safe fats and waxes as glossing agents.

In the meaning of the invention, all the pharmaceutically commoncapsules such as gelatin hard capsules, soft gelatin capsules, starchcapsules are possible as capsules. The capsules may be filled withpowders, granulates, pellets or tablets. In general, all thepharmaceutically common solid, liquid and semi-solid formulations may befilled into the capsules of the invention.

For micro-encapsulating the active substance or formulations of theactive substance, all the polymeric film-forming agents mentioned abovemay be used according to the invention. Here, the polymers may be usedalone as well as in mixtures of multiple polymers, and also togetherwith other adjuvants, if necessary.

In the following, the invention will be illustrated by way ofembodiments which are not intended as limitation.

For example, The ibandronate active substance is employed in amounts of0.1-100 mg per single dosage unit. Preferably, the dosage is at leastca. 1 mg, 5 mg, 10 mg, or 20 mg as lower limit for the amount of activesubstance in a single administration form. The upper limit is about 250mg, particularly 100 mg and 50 mg, respectively.

EXAMPLE 1

Ibandronate-containing core: Ibandronate dose [mg] in 200 mg tabletcore: 10.0 20.0 50.0 Ibandronate-free coat [mg]:Methylhydroxypropylcellulose 5.1425 5.1425 5.1425 Titanium dioxide2.4650 2.4650 2.4650 Macrogol 1.5000 1.5000 1.5000 Talc 0.8925 0.89250.8925 Total film coated 10.0000 10.0000 10.0000

Film-coating is carried out in common apparatus. Coating conditions:tablet charge 140 kg; feed air temperature: 60° C.

EXAMPLE 2

Ibandronate-containing core: Ibandronate dose in 100 mg tablet core[mg]: 0.1 2.5 5.0 Ibandronate-free coat [mg]:Methylhydroxypropylcellulose 2.057 2.057 2.057 Titanium dioxide 0.9860.986 0.986 Macrogol 0.600 0.600 0.600 Talc 0.357 0.357 0.357 Total filmcoated 4.000 4.000 4.000

Film-coating in a conventional 250 I tablet coating tank. Coatingconditions: tablet charge 144 kg.

EXAMPLE 3

Ibandronate-containing core: Ibandronate dose [mg] in 200 mg tabletcore: 10.0 20.0 50.0 Ibandronate-free coat [mg]: Talc 2.00 2.00 2.00Lactose 1.40 1.40 1.40 Methylhydroxypropylcellulose 0.80 0.80 0.80Titanium dioxide 0.80 0.80 0.80 Macrogol 0.40 0.40 0.40 Ethyl methylmethacrylate copolymer* 0.04 0.04 0.04 Polysorbate 0.04 0.04 0.04 Totalfilm coated 5.48 5.48 5.48*Employed in the form of Eudragit ™ NE 30 D as an aqueous dispersion.

Film-coating in a conventional 15 I tablet coating tank. Coatingconditions: tablet charge 13.0 kg.

EXAMPLE 4

Ibandronate-containing core: Ibandronate dose in 74 mg tablet core [mg]:20 Ibandronate-free coat [mg]: Methylhydroxypropylcellulose phthalate4.580 Triacetin 1.374 Polysorbate 0.046 Total film coated 6.000

Film-coating in a conventional 5 I tablet coating. Coating conditions:tablet charge 0.25 kg.

EXAMPLE 5

Ibandronate-containing core: Ibandronate dose [mg] in 86 mg tablet core:10.000 Ibandronate-free coat [mg]: Saccharose 37.844 White clay 8.138Talc 1.000 Macrogol 2.848 Glucose syrup 2.035 Titanium dioxide 1.628Polyvidone 0.407 Montan glycol wax 0.100 Total tablet coating applied54.000

Tablet coating in a conventional 15 I tablet coating tank with dip pipe.

EXAMPLE 6

Ibandronate-containing core:

Ibandronate dose [mg] in 400 mg granulate: 20 mg and 50 mg.

Ibandronate-free coat [mg]: hard gelatin two-piece capsule, size 0,white opaque. Encapsulation of the drug mass performed on aHarro-Höfliger type encapsulating machine.

EXAMPLE 7

Ibandronate in laminated tablet Ibandronate-containing core: Finalweight:  86 mg Format of core:  7 mm in diameter, plane, with facettesIbandronate dose in tablet core:  10 mg Ibandronate-free coat: Lactose270 mg Microcrystalline cellulose:  90 mg Pressing tool:  12 mm indiameter Final weight of laminated tablet: 446 mgPressing by means of a hand press using conventional procedures.

1-20. (canceled)
 21. A method of treating a bone disease in a patient inneed thereof, comprising orally administering to the patient apharmaceutical formulation comprising (a) a core containing a bonedisease treating effective amount of ibandronate and (b) a coating whichis free of ibandronate, wherein the coating dissolves or is separatedfrom the core during contact with digestive solution in the patient'sstomach, wherein the pharmaceutical formulation avoids release ofibandronate in the esophagus, and wherein at least 30% of theadministered amount of ibandronate is released from the pharmaceuticalformulation into the stomach.
 22. The method of claim 21, wherein thebone disease is related to a disorder in calcium metabolism.
 23. Themethod of claim 21, wherein the bone disease is selected from the groupconsisting of hypercalcemia, osteoporosis, tumor osteolysis and Paget'sdisease.
 24. The method of claim 21, wherein at least 75% of theadministered amount of ibandronate is released from the pharmaceuticalformulation into the stomach.
 25. The method of claim 21, wherein atleast 85% of the administered amount of ibandronate is released from thepharmaceutical formulation into the stomach.
 26. The method of claim 21,wherein at least 30% of the administered amount of ibandronate isreleased from the pharmaceutical formulation into the stomach in lessthan 2 hours after the pharmaceutical formulation contacts the digestivesolution in the patient's stomach.
 27. The method of claim 21, whereinat least 75% of the administered amount of ibandronate is released fromthe pharmaceutical formulation into the stomach in less than 2 hoursafter the pharmaceutical formulation contacts the digestive solution inthe patient's stomach.
 28. The method of claim 21, wherein at least 85%of the administered amount of ibandronate is released from thepharmaceutical formulation into the stomach in less than 2 hours afterthe pharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 29. The method of claim 21, wherein at least 30% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach in less than 1 hour afterthe pharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 30. The method of claim 21, wherein at least 75% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach in less than 1 hour afterthe pharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 31. The method of claim 21, wherein at least 85% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach in less than 1 hour afterthe pharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 32. The method of claim 21, wherein at least 30% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach 1-30 minutes after thepharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 33. The method of claim 21, wherein at least 75% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach 1-30 minutes after thepharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 34. The method of claim 21, wherein at least 85% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach 1-30 minutes after thepharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 35. The method of claim 21, wherein about 80-90% ofthe administered amount of ibandronate is released from thepharmaceutical formulation into the stomach within 15 minutes after thepharmaceutical formulation contacts the digestive solution in thepatient's stomach.
 36. The method of claim 21, wherein the coatingcomprises at least one member selected from the group consisting ofcellulose, cellulose derivatives, dextrins, starches, starchderivatives, carbohydrate polymers, natural gums, polyacrylic acid,polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone,polymethacrylates, polymethacrylate derivates, chitosan, chitosanderivates, shellac, shellac derivates, fats and waxes.
 37. The method ofclaim 21, wherein the coating comprises at least one cellulosederivative selected from the group consisting of methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose, sodiumcarboxymethylcellulose and ethylcellulose.
 38. The method of claim 21,wherein the coating comprises at least one polymethacrylate derivativeselected from the group consisting of a cationic copolymer ofdimethylaminoethyl methacrylate with neutral methacrylic esters, acopolymer of acrylic and methacrylic esters and a copolymer of ethylacrylate and methyl methacrylate.
 39. The method of claim 21, whereinthe coating comprises at least one member selected from the groupconsisting of an anionic copolymer of methacrylic acid and methylmethacrylate, cellulose acetate phthalate, cellulose acetatetrimelliatate, methylhydroxypropylcellulose phthalate and polyvinylacetate phthalate.
 40. In a method of treating bone disease in a patientin need thereof, wherein said method comprises orally administering to apatient a pharmaceutical formulation containing ibandronate, theimprovement comprising (a) a core containing a bone disease treatingeffective amount of ibandronate and (b) a coating which is free ofibandronate surrounding the core, wherein the coating dissolves or isseparated from the core during contact with digestive solution in thepatient's stomach, and wherein the coating prevents irritation andulcerations of the esophagus, and wherein at least 30% of theadministered amount of ibandronate is released from the pharmaceuticalformulation into the stomach.
 41. A method of treating a bone disease ina patient in need thereof, comprising orally administering to thepatient a pharmaceutical formulation comprising (a) a core containing abone disease treating effective amount of ibandronate and (b) a coatingwhich is free of ibandronate, wherein the thickness and type of thecoating is chosen so that when the pharmaceutical formulation isadministered orally to the patient, the r lease of the ibandronate inthe esophagus is avoided, the coating dissolves or is separated from thecore during contact with digestive solution in the patient's stomach,and at least 30% of the administered amount of ibandronate is releasedfrom the pharmaceutical formulation into the stomach.